Field of the Invention
The invention relates to methods for treating central nervous system lesions in a mammal. The invention further relates to a method for using neural stem cells to induce formation of functional synaptic junctions and corticospinal regeneration in the spinal cord.
Background Information
The mammalian spinal cord shows little spontaneous recovery after injury. Furthermore, although regeneration of damaged spinal cord tissues (e.g., axons and neurons) can sometimes be induced to a degree through treatment, formation of functional synaptic junctions between axonal termini and adjacent neurons remains elusive.
The degree of motor function loss varies with the identity of the damaged tissue and the extent of damage incurred, as well as with species. For example, the rubrospinal tract influences movement through direct and reciprocal spinal motor projections that reflect activity of the rubro-cortico-cerebellar premotor pathway. The vestibulospinal and reticulospinal tracts affect postural control and balance during locomotion. Specialization in the vestibular system in particular has been important for the evolution of bipedal locomotion in humans. However, impairments in voluntary motor function after spinal cord injury in humans are most often attributed to disruption of corticospinal tract (CST) projections.
It has long been assumed that elicitation of long-distance axonal regeneration in the adult spinal cord would require modification of the inhibitory CNS milieu. Research over the last several decades has revealed numerous molecular mechanisms in the environment of the adult central nervous system (CNS) that contribute to the failure of axonal regeneration after injury. For example, myelin-associated proteins are released which inhibit axonal growth, inhibitory extracellular matrix molecules become deposited around injury sites, and positive environmental stimuli, such as growth factors, are absent.
The observation that at least some classes of adult CNS axons can grow over long distances in peripheral nerve bridges (but not within the CNS) supports the view that the adult CNS environment is inhibitory. However, some studies indicate that neuron-intrinsic mechanisms also contribute to axonal growth failure in the adult CNS. The extent to which therapies directed to modifying neuron-intrinsic mechanisms alone could overcome the inhibitory growth environment of the adult CNS is controversial. Conventional wisdom in the art, however, is that modification of the inhibitory environment is essential to correcting the neuronal damage and functional deficits which follow CNS injury (e.g., to the spinal cord).
To that end, various interventions have been considered to modify the inhibitory environment in the spinal cord, outside of a lesion site. Examples include immunosupression, administration of myelin-associated inhibitors (e.g., MAG and nogo) and/or targeting certain CNS receptors with, for example, acetylcholine or extracellular matrix molecules (e.g., laminin, immunoglobulins) and exposing the cord environment to neurotrophic factors.
To date, however, such interventions have failed to restore axonal growth and function to damaged, diseased or otherwise degenerated CNS neuronal populations. A need, therefore, exists for an effective therapy for CNS lesions.